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IL CAMPUS Finalità Storia Organizzazione Docenti Concorsi OFFERTA FORMATIVA Corsi di laurea Specializzazioni Master Formazione Continua STUDENTI Orientamento Ammissioni Segreteria Servizi Tutorato Borse di studio Mobilità POLICLINICO Struttura Visite Ambulatoriali Ricoveri e Degenza URP RICERCA Premessa Aree e Dipartimenti Bandi Dottorati AGORA' Biblioteca Cappellania Alumni Enti Sostenitori	Ricerca>Progetti>Biomed2>EU COMMISSION BIOMED 2 FINAL REPORT PART A 1. Title of the project - Impact of autism-related peptides and 5-HT system manipulations on cortical development and plasticity 2. Contract number: - BMH4-CT96-0730 - Supplementary Agreement N° 001 (transfer of the contract from Universidad Autonoma de Madrid to Universidad de Navarra) 3. Official contractual period: - 1 July 1996-30 June 1999 4. Coordinator: Dr. Flavio Keller Laboratory of Neuroscience Università “Campus Bio-Medico” V. Longoni 83 I-00155 Rome, Italy Tel.: +396 22 54 13 35 Fax: +396 22 54 14 56 E-mail: f.keller@unicampus.it 5. Participants: Dr. K.P. Lesch Department of Psychiatry University of Würzburg Sanderring 2 D-97070 Würzburg Tel.: +49 931 2031 Fax: +49 931 203 425 E-mail: kplesch@mail.uni-wuerzburg-de Dr. K.L. Reichelt Institute of Pediatric Research University of Oslo Rikshospitalet N-0027 Oslo Tel.: +47 22 86 9045 Fax: +47 22 86 9117 E-mail: K.L.Reichelt@rh.uio.no Dr. J.M. Giménez-Amaya Department of Anatomy Faculty of Medicine University of Navarra 31030 Pamplona Tel.: +34 948 425 600 Fax: +34 948 425 649 E-mail: jmga@unav.es Dr. R. Cortese IRBM Via Pontina, km 30,600 00040 Pomezia (Roma) Tel.: +396 9109 3201 Fax: +396 9109 3654 E-mail: cortese@irbm.it 6. Funding: 205.000 ECU 7. Abstract: Autism is a major psychiatric disorder with early onset in life and strong psychosocial impact, that severely affects individuals and their families. Up to today, both the etiology and the pathogenesis of the disease remain obscure. Autism has probably many different causes. There is a growing body of evidence that autism has a strong genetic component. Serotonin (5-HT) has long been suspected to be involved in the pathogenesis of autistic disorder. Autistic children tend to have elevated 5-HT blood levels. They also tend to excrete abnormally high amounts of low molecular weight peptides in their urine. We have found that some of these peptides are potent stimulators of 5-HT transport. Alteration of 5-HT metabolism in autism may be induced by the accumulation of 5-HT transport-stimulating peptides. Identification of urinary peptides may lead to early diagnosis of patients with the disorder. This project has been developed to thoroughly assess the role of 5-HT in brain development, using pharmacological and molecular genetical approaches, and to isolate and characterize 5-HT uptake-stimulating peptides from autistic patients. The main results and conclusions of the project are the following: 1) Increased 5-HT extracellular levels lead to subtle alterations of cortical circuitry in the developing brain; persistently high levels of extracellular 5-HT may lead to neurotoxic damage in the adult and aging brain, possibly through lipid peroxidation. 2) Autistic patients excrete abnormally high levels of peptides in their urine; one of these peptides, a tripeptide, is a potent stimulator of 5-HT transport. This peptide may be involved in the pathogenesis of autistic disorder and be the cause of high 5-HT blood levels observed in autistic patients. A monoclonal antibody against the tripeptide has been generated and could be used for the setup of an immunological screening assay in urine or plasma, possibly allowing early identification of subjects who are at risk to develop the disorder (i.e. before clinical symptoms become apparent). There is no doubt that these patients would benefit from early rehabilitation programs. 3) A new candidate gene for autistic disorder has been identified on the basis of the structure of urinary peptides found in autistic patients, and is presently being characterized. 4) The structure of the 5-HT transporter gene promoter has been completely clarified. This may lead to novel, efficient and safe strategies of targeting therapeutic genes to neurons or glial cells, which is a key goal of gene therapy. 8. Project related publications: NB: Authors and Institutions who are partners of the Biomed project are highlighted in bold publications in peer reviewed journals IMPLANTS FOR SUSTAINED DRUG RELEASE OVER THE SOMATOSENSORY CORTEX OF THE NEWBORN RAT: A COMPARISON OF MATERIALS AND SURGICAL PROCEDURES A.M. Persico, E. Calia and F. Keller Lab. of Neuroscience, Università Campus Bio-Medico di Roma, Italy J. Neurosci. Meth. 76:105-113 (1997) GENE STRUCTURE AND 5’-FLANKING REGULATORY REGION OF THE MURINE SEROTONIN TRANSPORTER D. Bengel, A. Heils, S. Petri, M. Seemann, K. Glatz, A. Andrews, D.L. Murphy, K.P. Lesch Department of Psychiatry, University of Würzburg, Germany Laboratory of Clinical Science, NIMH, Bethesda, Maryland, U.S.A. Mol. Brain Res. 44:286-292 (1997) Altered brain serotonin (5-HT) homeostasis and locomotor insensitivity to MDMA ("ecstasy") in 5-HTT-deficient mice. D. Bengel, D.L. Murphy, A.M. Andrews, C.H. Wichems, D. Feltner, A. Heils, R. Mössner, H. Westphal, K.P. Lesch Laboratory of Clinical Science, NIMH, Bethesda, Maryland, U.S.A. Laboratory of Mammalian Genes and Development, NICHHD, Bethesda, Maryland, U.S.A. Department of Psychiatry, University of Würzburg, Germany Mol Pharmacol 53:649-655 (1998) FUNCTIONAL CHARACTERIZATION OF THE MURINE SEROTONIN TRANSPORTER GENE PROMOTER IN SEROTONERGIC RAPHE NEURONS A. Heils, C. Wichems, R. Mössner, S. Petri, K. Glatz, D. Bengel, D.L. Murphy, K.P. Lesch Department of Psychiatry, University of Würzburg, Germany Laboratory of Clinical Science, NIMH, Bethesda, Maryland, U.S.A. J Neurochem 70:932-939 (1998) SEROTONIN UPTAKE STIMULATING PEPTIDE FOUND IN PLASMA OF NORMAL INDIVIDUALS AND IN SOME AUTISTIC URINES O.S. Pedersen, Y. Liu, K.L. Reichelt University of Oslo, Rikshospitalet, Oslo, Norway J Pept Res 53:641-646 (1999) SEROTONIN TRANSPORTER PROMOTER POLYMORPHISM INFLUENCES TOPOGRAPHY OF INHIBITORY MOTOR CONTROL A.S. Fallgatter, S. Jatzke, A. Bartsch, B. Hamelbeck, K.P. Lesch Department of Psychiatry, University of Würzburg, Germany Int.J. Neuropsychopham. 2:115-120 (1999) ADAPTIVE CHANGES OF SEROTONIN 5-HT2A RECEPTORS IN MICE LACKING THE SEROTONIN TRANSPORTER A. Rioux, V. Fabre, K.P. Lesch, R. Moessner, D. Murphy, L. Lanfumey, M. Hamon, M.P. Martres INSERM U288, Faculté de Médecine Pitié-Salpetrière, Paris Department of Psychiatry, University of Würzburg, Germany Laboratory of Clinical Science, NIMH, Bethesda, Maryland, U.S.A. LACK OF ASSOCIATION BEWTEEN SEROTONIN TRANSPORTER GENE PROMOTER VARIANTS AND AUTISTIC DISORDER IN TWO ETHNICALLY-DISTINCT SAMPLES E. Mengual 1, J. Arellano 2, A.M. Persico 3, F. Keller 3, D.L. Murphy 4, K.P. Lesch 5, J.M. Giménez-Amaya 1 and J. DeFelipe 2. 1) Depto. de Anatomía, Facultad de Medicina, Universidad de Navarra, Spain 2) Instituto Cajal, CSIC, Madrid 28002, Spain 3) Lab. di Neuroscienze, Libera Università "Campus Bio-Medico" di Roma, Italy 4) Lab of Clinical Science, Natl Inst. Mental Health, Bethesda, MD 20892-1264, USA 5) Dept. Psychiatry, University of Würzburg, 97080 Würzburg, Germany Submitted (1999) LACK OF BARRELS BUT INTACT INTRINSIC SYNAPTIC CIRCUITS IN SOMATOSENSORY CORTICAL LAYER IV OF SEROTONIN TRANSPORTER KNOCK-OUT MICE E. Mengual 1, J. Arellano 2, A.M. Persico 3, F. Keller 3, D.L. Murphy 4, K.P. Lesch 5, J.M. Giménez-Amaya 1 and J. DeFelipe 2. 1) Depto. de Anatomía, Facultad de Medicina, Universidad de Navarra, Spain 2) Instituto Cajal, CSIC, Madrid 28002, Spain 3) Lab. di Neuroscienze, Libera Università "Campus Bio-Medico" di Roma, Italy 4) Lab of Clinical Science, Natl Inst. Mental Health, Bethesda, MD 20892-1264, USA 5) Dept. Psychiatry, University of Würzburg, 97080 Würzburg, Germany Submitted (1999) 5-HT DEPLETION AND BARREL CORTEX DEVELOPMENT: IMPACT OF GROWTH IMPAIRMENT VS 5-HT EFFECTS ON THALAMOCORTICAL ENDINGS A.M. Persico, C. Altamura, E. Calia, S. Puglisi-Allegra, R. Ventura, F. Lucchese, F. Keller Lab. of Neuroscience, Libera Università Campus Bio-Medico di Roma, Italy Dept. of Psychology, Università “La Sapienza”, Rome, Italy Submitted (1999) SYNTHETIC TRIPEPTIDE AUGMENTS THE AGONIST INDUCED INTRACELLULAR CALCIUM INCREEASE O.S. Pedersen., K.L. Reichelt University of Oslo, Rikshospitalet, Oslo, Norway Submitted (1999) A SEROTONIN UPTAKE STIMULATING TETRAPEPTIDE FOUND IN URINES FROM ADHD CHILDREN AND SOME AUTISTIC PATIENTS Y. Liu, K.L. Reichelt University of Oslo, Rikshospitalet, Oslo, Norway Submitted (1999) other publications in scientific journals or book chapters ---- international meeting abstracts (oral presentations, posters) Persistent reduction in whisker barrel areas following systemic and local parachloroamphetamine-induced serotonin depletion in neonatal rats. F. Keller, A.M. Persico, E. Calia, S. Puglisi-Allegra Lab. of Neuroscience, Libera Università Campus Bio-Medico di Roma, Italy Dept. of Psychology, Università “La Sapienza”, Rome, Italy Soc. Neurosci. Abs. 22: 1357 (1996) PCA- and PCPA-induced reductions in cortical whisker barrel areas likely stem from malnutrition and/or direct damage of thalamocortical terminals, and not from serotonin-depletion. A.M. Persico, E. Calia, S. Puglisi-Allegra, F. Keller Lab. of Neuroscience, Libera Università Campus Bio-Medico di Roma, Italy Dept. of Psychology, Università “La Sapienza”, Rome, Italy Soc. Neurosci. Abs. 23:74 (1997) Alterations in neonatal barrel cortex and in the ageing brain of serotonin transporter knockout mice. A.M. Persico 1, A. Baldi 1, E. Calia 1, R. Moessner 2, K.P. Lesch 2, D.L. Murphy 3, F. Keller 1 1) Lab. di Neuroscienze, Libera Università "Campus Bio-Medico" di Roma, Italy 2) Dept. Psychiatry, University of Würzburg, 97080 Würzburg, Germany 3) Lab of Clinical Science, Natl Inst. Mental Health, Bethesda, MD 20892-1264, USA Soc. Neurosci. Abs., 24:1111 (1998) Serotonin uptake stimulating peptides extracted from the urines of autistic patients:potential significance for the pathogenesis of autistic disorder 1F. Keller, 1A.M. Persico, 1A. Baldi, 2K.L. Reichelt, 3A. Gonzalez 1) Lab. di Neuroscienze, Libera Università "Campus Bio-Medico" di Roma, Italy 2) University of Oslo, Rikshospitalet, Oslo, Norway 3) Dept. of Pharmacology, University of Cantabria, Santander, Spain Soc. Neurosci. Abs., 24:227 (1998) CYTOARCHITECTONIC ALTERATIONS IN PRIMARY SENSORY CORTICES OF ADULT SEROTONIN TRANSPORTER KNOCKOUT MICE 1A.M. Persico, 1A. Baldi, 2R. Moessner, 3D.L. Murphy, 2K.P. Lesch, 1F. Keller 1) Lab. di Neuroscienze, Libera Università "Campus Bio-Medico" di Roma, Italy 2) Dept. Psychiatry, University of Würzburg, 97080 Würzburg, Germany 3) Lab of Clinical Science, Natl Inst. Mental Health, Bethesda, MD 20892-1264, USA Soc. Neurosci. Abs, in press (1999) NO SIGNIFICANT ASSOCIATIONS BETWEEN 5-HT TRANSPORTER GENE VARIANTS AND AUTISTIC DISORDER OR 5-HT BLOOD LEVELS IN TWO ETHNICALLY-DISTINCT SAMPLES 1F. Keller, 1A.M. Persico, 2R. Militerni, 2C. Bravaccio, 3C. Schneider, 3R. Melmed, 4S. Puglisi-Allegra, 4T. Pascucci, 1V. Damiani and 1A. Baldi. 1) Lab. of Neuroscience, Univ. “Campus Bio-Medico”, Rome, Italy; 2) Dept. of Child Neuropsychiatry, II Univ. of Naples, Naples, Italy; 3) Southwest Autism Research Center, Phoenix, AZ; 4) Dept. of Psychology, Univ. “La Sapienza”, Rome, Italy. Soc. Neurosci. Abs., in press (1999) patents An Italian patent on the structure of serotonin uptake-stimulating peptides, and on diagnosis of autism based on these peptides, has been filed on August 4, 1998 (N° MI98A 001834). The extension of the Italian patent to European countries has been filed on July 30, 1999. Listed Inventors are: Dr. F. Keller (Libera Università Campus Bio-Medico, Rome, Italy) Dr. A.M. Persico (Libera Università Campus Bio-Medico, Rome, Italy) Dr. O.S. Pedersen (Rikshospitalet, Oslo, Norway) Dr. K.L. Reichelt (Rikshospitalet, Oslo, Norway) 9. Deliverables for exploitation: - Purification procedure of 5-HT transport-stimulating peptides - Structure of 5-HT transport-stimulating peptides - Monoclonal antibody against a 5-HT transport-stimulating tripeptide - 5-HTT knock-out mouse - Structure of the 5-HTT gene promoter - Synthetic 5-HTT stimulating tripeptide (Bachem AG, Cat.# H-3858)